Antigen specific immunity is mediated by B and T lymphocytes. This characteristic has allowed their use in development of novel therapeutics such as monoclonal antibodies and cancer killing LAK and TIL cells. These cells may also play a role in limiting the efficacy of gene therapies since expression of a novel gene product may result in stimulation of immunity and consequent rejction of cells expressing the therapuetic gene product. Also, neoplastic transformation of these cells results in a large proportion of human leukemias and lymphomas. Because of the importance of these cells as therapuetic tools and in disease, we have been studying molecular mechanisms governing lymphoid cell differentiation and neoplasia using several approaches. (1) We use tumors representing different stages of differentiation to further understand the process of lymphoid cell development and to compare and contrast the oncogenic events leading to tumors in different cell lineages. Tumorigenesis can be targeted to the B or T cell lineage by overexpressing the myc oncogene using enhancers specific for immunoglobulin genes or the T cell receptor genes. We have been studying the process of neoplastic transformation in precursor B cells using an RT-PCR assay capable of quantifying expression of 20 candidate oncogenes. We have isolated normal, preneoplastic, and neoplastic preB cells using tissue culture methods and preB cell tumors. We have found that RNA levels of several oncogenes including c-myc, p53, and c-myb increase in level of expression as the cell undergo sequential steps in tumorigenesis and become more fully malignant. (2) Genetic background influences susceptibility to cancer. Recombinant retroviruses carrying two oncogenes cause tumors in Balb/c mice but do not give tumors in DBA/2 mice. We investigate the genetic differences in these two strains using in vitro infection of normal preB cell lines from DBA/2 or Balb/c mice. In contrast to in vivo results, preB cell lymphomas can be established from mice of both strains. These tumors are preB cells but lose IL-7 and stromal cell dependence. They yeild solid tumors with a 10 to 20 day latency when injected into both strains. These results demonstrate that preB cells from both tumor resistant and tumor susceptible strains can indeed be infected by virus and suggests that the genetic differences between strains may be external to infected preB cells so may include immune surveillance differences. (3) We have used Ebeta-myc mice (myc gene expression conttrolled by the TCRbeta enhancer) to determine the influence of the myc gene on T cell development in the thymus by examining effects on positive selection, negative selection, and co-receptor determination. Myc gene overexpression seems to leave negative selection intact, to disrupt positive selection, and to favor differentiation into the CD4 lineage.